(12) United States Patent (10) Patent No.: US 8,859,556 B2 Svensson Et Al
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US008859556B2 (12) United States Patent (10) Patent No.: US 8,859,556 B2 Svensson et al. (45) Date of Patent: Oct. 14, 2014 (54) TRPA1 RECEPTOR ANTAGONIST OTHER PUBLICATIONS (75) Inventors: Mats Svensson, Sodertalje (SE); Dirk Bandell et al., “Noxious Cold Ion Channel TRPAl Is Activated by Weigelt, Ronninge (SE) Pungent Compounds and Bradykinin’. Neuron 2004, 41(6), 849 857. (73) Assignee: Acturum Life Science AB, Solna (SE) Bautista et al. “TRPAl Mediates the Inflammatory Actions of Envi ronmental Irritants and Proalgesic Agents”. Cell 2006, 124(6), 1269 (*) Notice: Subject to any disclaimer, the term of this 1282. patent is extended or adjusted under 35 Jaquemar et al., “An Ankyrin-like Protein with Transmembrane U.S.C. 154(b) by 0 days. Domains Is Specifically Lost after Oncogenic Transformation of Human Fibroblasts”, J Biol Chem 1999, 274(11), 7325-7333. (21) Appl. No.: 13/878,862 Kremeyer et al. "A Gain-of-Function Mutation in TRPAl Causes Familial Episodic Pain Syndrome'. Neuron 2010, 66(5), 671-680. (22) PCT Filed: Oct. 11, 2011 Kwan et al., “TRPA1 Contributes to Cold, Mechanical, and Chemical Nociception but Is Not Essential for Hair-Cell Transduction”, Neu (86). PCT No.: PCT/SE2O11AOS1213 ron 2006, 50(2), 277-289. McGaraughty et al. “TRPA1 modulation of spontaneous and S371 (c)(1), mechanically evoked firing of spinal neurons in uninjured, (2), (4) Date: Jun. 19, 2013 osteoarthritic, and inflamed rats'. Molecular Pain 2010, 6:14. McNamara et al. “TRPA1 mediates formalin-induced pain'. Proc (87) PCT Pub. No.: WO2012/050512 Natl AcadSci USA 2007, 104(33), 13525-13530. PCT Pub. Date: Apr. 19, 2012 Primary Examiner — Kahsay Habte (65) Prior Publication Data (74) Attorney, Agent, or Firm — Baker & Hostetler LLP US 2014/0148466A1 May 29, 2014 (57) ABSTRACT Related U.S. Application Data A compound of Formula (I), pharmaceutically acceptable salts thereof, enantiomers, or mixtures thereof: pharmaceuti (60) Provisional application No. 61/392,130, filed on Oct. cal compositions containing said compounds, enantiomers or 12, 2010. mixtures; processes for making said compounds, enanti (51) Int. Cl. omers or mixtures; the use of said compounds, enantiomers or CO7D 40/4 (2006.01) mixtures; and medicaments containing the same for treatment C07D 213/74 (2006.01) of pain and other conditions; and methods of treating pain and A6 IK3I/44 (2006.01) other conditions with the same. (52) U.S. Cl. USPC ...................................... 514/253.01:544/360 (58) Field of Classification Search (I) USPC ...................................... 544/360; 514/253.01 See application file for complete search history. (56) References Cited U.S. PATENT DOCUMENTS 2009,0176883 A1 7/2009 Perner et al. 2009/0325987 A1 12/2009 Muthuppalniappan et al. FOREIGN PATENT DOCUMENTS WO WO2005/O12287 2, 2005 WO WO2OO7 O73505 6, 2007 WO WO2008/007103 1, 2008 WO WO2010/075353 T 2010 7 Claims, 2 Drawing Sheets U.S. Patent Oct. 14, 2014 Sheet 1 of 2 US 8,859,556 B2 Figure 1. Counts 1 OOO 500 10 20 30 Position (2Theta) U.S. Patent Oct. 14, 2014 Sheet 2 of 2 US 8,859,556 B2 Figure 2. AbS. 1) Experimental VCD spectrum of example 6 | -- /N ^\ r -\'v. \ ^- A -- - - - - -/A \- y V ;—-y 2) Inversion - Of calculated VCD?'--/--/ spectrum (4)N/--- . A.\J n \W. /N--------Y. --. /. : 3) Experimental VCD spectrum of example 7 i --- rt-:''- - ------ ,--- --- ---...-- i ''. 4) Calculated VCD Spe trum for fragment (II) y- -- - - -- W ---, r - \/\----, | Ay A- \- ill- v/ -- --- 1700 1600 1500 1400 1300 1200 1100 1000 900 Wavenumbers (cm) VCD Experimental and Calculated Spectra. US 8,859,556 B2 1. 2 TRPA1 RECEPTOR ANTAGONST pensity to work as an analgesic in vivo. An object of the present invention is therefore to provide new, improved and FIELD OF THE INVENTION useful analgesics. The present invention relates to antagonists of the transient SUMMARY OF THE INVENTION receptor potential (TRP) family of ion channels. The present Non-selective cation channel TRPA1 antagonists are invention also provides compositions comprising Such described. The described antagonists can be used for treating antagonists and methods therewith for treating diseases medi pain and other conditions. Medical conditions which are ated by the transient receptor potential (TRP) family of ion mediated by TRPA1 antagonists include asthma, pertussis channels. Particularly, the present invention is related to non 10 and nicotine addiction. selective cation channel TRPA1 antagonist compounds use ful for treating pain and other specific disorders. BRIEF DESCRIPTION OF THE DRAWINGS BACKGROUND FIG. 1 shows an X-Ray Powder Diffraction (XRPD) pat 15 tern for the compound of Example 6. The transient receptor potential (TRP) family of ion chan FIG. 2 shows VCD Spectra for compounds. nels are often found to be sensors of multiple chemical and physical stimuli (temperature, Smell, taste and noxious DETAILED DESCRIPTION OF THE INVENTION chemicals). Particularly, the non-selective cation channel TRPA1 (transient receptor potential ankyrin-repeat 1), origi The present invention thus provides new antagonists of the nally cloned as an ankyrin-like protein (Jaquemar et al 1999, non-selective cation channel TRPA1. The new antagonists J Biol Chem 274:7325-7333), is activated by multiple pun can be used for, amongst other things, treating pain. Further gent and pro-algesic compounds (Bandell et al 2004, Neuron medical conditions which are mediated by TRPA1 antago 41: 849-857). Recent reviews on TRPA1 as pharmaceutical nists include asthma, pertussis and nicotine addiction. target have been published by Rechet al. (Future Med. Chem. 25 In a first aspect, the present invention provides a compound 2010: 843-838) and by Baraldi et al (J. Med. Chem. 2010, of Formula (I), a pharmaceutically acceptable salt thereof, 5085-2107). TRPA1 is highly expressed in a subset of C-fiber enantiomer, or mixture thereof: nociceptors in the peripheral nerve system (Kobayashi et al (I) 2005, J. Comp Neurol 493(4):596-606). When activated TRPA1 permits the conduction ofcations (primarily Ca" and 30 2 Na") from the extra cellular environment into the cell, thereby depolarizing the membrane potential and affecting calcium homeostasis in the primary afferents. Depolarization primary nerve terminals lead to action potential firing and conse quently increased pain sensation and hyperalgesia in man and 35 rodent experimental models (Jiang and Gebhart 1998, Pain 77(3):305-13; Cervero and Laird 1996, Pain 68(1):13–23). The pungent ingredient in mustard oil: allyl isothiocyanate (AITC), concentration dependently activates TRPA1 in vitro measured both on sodium current and calcium influx. Further, 40 AITC also excites small diameter afferent fibers (Reeh 1986, It will be understood that as a compound of the present Brain Res 384:42-50) and indeed topical application of AITC invention contains one chiral centers, the compound may induces pain and hyperalgesia in man (Namer et al 2005, exist in, and be isolated as, enantiomeric forms, or as a race Neuroreport 16(9):955-959). Recently TRPA1 knock out mic mixture. The present invention includes any possible (KO) mice were described to have lost AITC sensitivity and 45 enantiomers, racemates or mixtures thereof, of a compound display severely impaired bradykinin pain response signal of Formula (I). The optically active forms of the compound of ling (Kwan 2006, Neuron 50(2):277-289; Bautista 2006, Cell the invention may be prepared, for example, by chiral chro 124(6):1269-1282). Formalin, which is a mixture of metha matographic separation of a racemate, by synthesis from opti nol, water and formaldehyde is a widely used rodent model cally active starting materials or by asymmetric synthesis for evaluating analgesic compounds in vivo. TRPA1 is acti 50 based on the procedures described thereafter. vated by formaldehyde in vitro and recently it was shown that One embodiment of the present invention is the (R) enan TRPA1 KO mice almost have their response to formalin/ tiomer of a compound of Formula (I) having the following formaldehyde abolished (McNamara et al 2007, Proc Natl Structure: AcadSci USA 104(33):13525-13530). A Hydra Biosciences proprietary compound (HCO30031) is a TRPA1 antagonist in 55 vitro and has been shown to alleviate the formalin induced 2 pain behaviour in a dose dependant way (McNamara 2007, Proc Natl Acad Sci USA 104(33):13525-13530 and WO2007/073505A2). An Abbott proprietary compound (US l 2009/0176883 and McGaraughty et al., Molecular Pain 2010 r^- 6:14) with in vitro effect on TRPA1 showed to have in vivo 60 N Nu O effect in a rat osteoarthritis pain model as well as a number of Glenmark proprietary compounds (US 2009/0325987) showed in several in vivo pain models. It has also been shown l that a mutation in TRPA1 causes FEPS (“Familial Episodic Pain Syndrome', Kremeyeretal, Neuron 2010, 66:671-680). 65 It is therefore suggested that in vitro inhibition of the TRPA1 It will also be understood that a compound of the present calcium and Sodium influx will determine a compound's pro invention may exist in Solvated, for example hydrated, as well US 8,859,556 B2 3 4 as unsolvated forms. It will further be understood that the tive pain, inflammatory pain, central pain, central and periph present invention encompasses all such solvated forms of the eral neuropathic pain, central and peripheral neurogenic pain, compound of the Formula (I). central and peripheral neuralgia, chronic tendinitis, low back Within the scope of the invention are also salts of the pain, postoperative pain, peripheral neuropathy, visceral compound of the Formula (I). Generally, pharmaceutically pain, pelvic pain, allodynia, anesthesia dolorosa, causalgia, acceptable salts of compound of the present invention may be dysesthesia, fibromyalgia, hyperalgesia, hyperesthesia, obtained using standard procedures well known in the art, for hyperpathia, ischemic pain, Sciatic pain, pain associated with example by reacting a sufficiently basic compound, for cystitis, including but not limited to interstitial cystitis, pain example an alkylamine with a suitable acid, for example, HCl associated with multiple Sclerosis, pain associated with or acetic acid, to afford a physiologically acceptable anion.